Atherosclerosis, i.e., hardening of the arteries, occurs when substances such as fat and cholesterol build up in the walls of arteries and form plaques. Plaque buildup narrows arteries, also referred to as stenosis, making them stiffer and more difficult for blood to flow. Pieces of plaque often break off forming an embolism blocking blood flow resulting in tissue damage which is a common cause of heart attacks and stroke. Carotid endarterectomy (CEA) is a surgical procedure used to prevent stroke, by correcting stenosis in the common carotid artery. Other procedures include endovascular angioplasty and stenting. Surgical procedures are expensive and undesirable. In addition, post-operative incidences of heart attack, stroke, and death are significant. Thus, there is a need for improved methods for treating and preventing atherosclerosis.
Atherosclerosis preferentially occurs in arterial regions exposed to disturbed flow (d-flow), in part, due to alterations in gene expression. Vascular endothelial cells respond to blood flow through mechanosensors, which transduce the mechanical force associated with flow (known as shear stress) into cell signaling events and ultimately bring about changes in gene expression. Disturbed-flow promotes while stable-flow inhibits atherogenesis, respectively, through differential regulation of pro-atherogenic and atheroprotective genes.
Ni et al. report the discovery of mechanosensitive genes in vivo using mouse carotid artery endothelium exposed to disturbed flow. Blood, 2010, 116(15): e66-73. Boon et al. report MicroRNA-29 in Aortic Dilation. Circ Res, 2011; 109:1115-1119. Maegdefessel et al. report inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development. J Clin Invest, 2012, 122(2):497-506.
Son et al. report the atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA by an XRN1-dependent manner induces endothelial inflammation and atherosclerosis. Nature Comm. 2013, 4:3000.
Reference cited herein are not an admission of prior art.